Similarities in certain metabolic characteristics of aged and transformed cells have been outlined in the original grant proposal. It has been pointed out also that several of these similarities appear to be related to the destabilized state of mitochondrial membranes in aged and malignant cells as compared to young, normal ones. Our previous studies have shown that destabilized mitochondrial membranes are susceptible to lipid peroxidation, the products of which (e.g., malonaldehyde) are known to interact with and modify proteins and nucleic acids. Work under this grant has shown that oxidized hemes and hemoproteins, and destablized iron-sulfur proteins, are the naturally occurring initiators of lipid peroxidation, and that superoxide anion is neither an initiator nor an obligatory intermediate for the process. Antioxidants inhibit lipid peroxidation in membranes and in model systems. Others have shown recently that antioxidants also decrease the incidence of several forms of malignancy and reduce carcinogen-induced chromosomal breaks in cultured leucocytes. Studies aimed at comparing the metabolic features of mitochondria from aged and malignant tissues have been initiated. Preliminary data on mitochondria isolated from Morris hepatomas, and from host livers as controls, have suggested that hepatoma mitochondria have a major defect, not in energy production and conservation (especially as regards sites II and III), but in their energy delivery system for ATP synthesis. The study of the molecular details of this important defect and comparisons with mitochondria from the livers of senescent rats are in progress and will continue during the third year of this grant.